Calcium sulphosuccinate composition and method of using same



United States Patent France, a French society No Drawing. Filed June 12,1961, Ser. No. 116,257 Claims priority, application France July 15, 19602 Claims. (Cl. 167--55) The present invention relates to pharmaceuticalcompositions for the treatment of calcium deficiencies and which, moregenerally, enable large amounts of calcium to be taken up by livingorganisms.

The novel pharmaceutical compositions according to the inventioncomprises, as active ingredient, the neutral or substantially neutralcalcium salts of sulphosuccinic acid HO SCH(COOH)-CH COOH.

These salts are obtained by the salification of the sulphosuccinic acidwith calcium oxide, calcium carbonate or any other basic calciumcompound so as to obtain a combination which, in solution, has a pHcompatible with the intended mode of administration. Thus forintramuscular and intravenous injections, the pH should be adjusted to avalue very close to 7, whilst for oral administration, salts having p-Hsfrom 5 to 8 may be used. This possibility of adjusting the pH of the calcium salts of sulphosuccinic acid about neutrality, arises from thestructure of sulphosuccinic acid which is a tribasic organic acid andacts as a butter in combination with strong bases.

Numerous calcium salts used therapeutically are salts of monobasic acidswhich do not have such a marked buffer effect and which, in solution,may develop injurious variations in pH, particularly under the influenceof hydrolyzing conditions.

The neutral calcium salt of sulphosuccinic acid has the empiricalformula C H Ca S and its structural formula is:

CHz.COO

/O O C.CH2 i 0 O C.CH-SOaCa-SOa-CH.C O 0 It exists in an anhydrous formand also in hydrated form with three molecules of water ofcrystallization.

Neutral calcium sulphosuccinate has the advantage of very greatsolubility in water; at ordinary temperature 100 g. of the trihydratedissolve in 100 g. of water. Concentrated solutions readily exhibitsupersaturation but the 10% solution withstands temperature variationsbetween 0 and 100 Without precipitation. Solutions of about 5%concentration, which are convenient for therapeutic use, have anindefinite stability on storage, whereas it is known that many calciumsalts used in medicine have to be kept in solution by more or lessreliable supersaturation devices.

Another advantage of neutral calcium sulphosuccinate is its high calciumcontent: 23.55% in the anhydrous salt, which enables large doses ofcalcium to be administered in a small volume. This is particularlyvaluable in the case of intramuscular injections.

The substantially neutral calcium salts of sulphosuccinic acid may beobtained by any suitable method. Thus one suitable method comprisesneutralizing sulphosuccinic acid in a boiling aqueous solution withexcess calcium carbonate, filtering the solution and separating thecalcium salt formed by evaporation or by precipitation with ethylalcohol in which it is insoluble.

The novel pharmaceutical composition according to the invention may beoffered in various forms: for example, ampoules of a solution indistilled sterlized water,

Patented June 30, 1964 suitable for administration by injection; adrinkable solution in a bottle; lozenges, pills, tablets of the powderedproduct; and suppositories made with an excipient such as cacao butteror polyoxyethylene waxes.

Neutral calcium sulphosuccinate is a very stable substance which isresistant to sterilization, preservation and to oxidation by the air. Ithas very little chemical reactivity and is compatible with other neutralmedicaments thus enabling it to be used medicinally in association withother ingredients favourable to the action of the calcium or having acomplementary physiological activity.

Neutral calcium sulphosuccinate shows very little toxicity in animals,however it is administered. In man there is the same absence of toxicityand an absence of even slight signs of intolerance. This remarkabletolerance is found in subjects who had proved unfavourably sensitive theother calcium medication. The association of treatment with calciumsulphosuccinate with other therapeutic treatments in numerous patientshas not revealed any incompatibility.

The therapeutic elfect of the pharmaceutical composition according tothe invention is excellent and is manifested, for example, by anincrease in weight with an increase in appetite, sthenic effect,improvement in the general condition, and/or improvement in theneurotonic condition.

The production of the new pharmaceutical composition, itspharmacological properties and its clinical effects on man areillustrated in the following illustrative examples.

Example 1 A 5% solution of neutral calcium sulphosuccinate in distilledwater was prepared and a certain number of sealed 5 cc. ampoules of thissolution were prepared. /3 of the ampoules were left in store as theywere. 'At the beginning of storage, the pH of the solution was 7.8 andat the end of days it had dropped slightly to become stationary at 7.2.Another third of the ampoules were sterilized at in this case the pHremained uniformly at 7.8, even after 90 days. Finally, the last thirdof the ampoules were sterilized at the pH likewise remains withoutvariation at 7.8. The sterilized ampoules stored 90 days did not showthe development of any colouration and the ultra-violet spectra likewiseremained identical. After sterilization and storage, a chemical analysiswas carried out to discover whether any chemical deterioration had takenplace. The test for carbonates proved negative; no decarboxylation ofthe product had taken place. The sulphite content which originally wasapproximately 1 part in a million (1 p.p.m.), remained unchanged; therewas therefore no hydrolysis of the sulphinic group in the sulphosuccinicacid.

These results show the stability of the solutions of neutral calciumsulphosuccinate to sterilization and to preservation, which conditionsare necessary for the production of a pharmaceutical product intendedfor injection.

Example 2 The toxicity of neutral calcium sulphosuccinate was determinedin mice by intravenous injection of a 5% solution into the tail vein ofthe animal. The dose was administered to batches of 12 mice at the rateof 2 to 8 centigrams respectively of dry product per 100 g. by weight.The lethal dose is found to be 50 (LD 50) which is 4.5 cg. to 100 g.weight of animal. This very limited toxicity is the known toxicity ofthe element calcium, the organic part of the molecule not playing anypart.

' is Example 3 The effect of the composition on calcemia in dogs wasstudied. A solution of neutral calcium sulphosuccinate was administeredby intrasaphenous means to four dogs, 3.4 mg. of anhydrous salt beingadministered per kg. of animal. The calcium in the blood was measuredseconds, 30 seconds, 1 hour and 3 hours after the injection. In the fourcases, practically no variation in the calcernia was found whichindicated assimilation and fixation of the calcium element.

Example 4 After a 5% solutionof neutral calcium sulphosuccinate had beeninjected by intrasaphenous means, the immediate action on the functionof some of the organs of dogs was examined. The doses were 2.5 mg, 5 mg.and 10 mg. per kg. of animal. In four animals, no modification was foundin: the respiration, the intestinal mobility, the renal volume, and theblood pressure. With a dose of mg. per kg. a slight acceleration in therespirationwas observed and a temporary cessation in the intestinalmovements, with more feeble resumption.

Example 5 A clinical'study of neutral calcium sulphosuccinate covered 35patients (16 men and 19 women) over a period of 90 days. The substanceadministered by venous means in a dose of 5 cc. or 10 cc. of 5% solution, the injections being carried out either every day or every otherday according to circumstances. The patient felt a slight impression ofburning under the tongue or at the level of the front part of the neckduring the injection; this elfect is comparable with that produced byother calcium derivatives injected by venous means, but is diminished inintensity. In none of the cases was there any accident or even a slightincident, and there was no lipothymic impression. No modification in theessential biological constants was observed and there was excellentgeneral tolerance even in delicate patients.

Example 6 Under the general conditions of treatment defined in Example5, the development of patients was followed, noting their generalcondition and their increase in weight.

Case J-Gastritis, following viral hepatitis with incipient cirrh'o is.Acalcium and hepato-therapeutic treatment was instituted for 40 days.After 60 days of treatment with calcium sulphosuccinate, there was anincrease in weight of 2 kg. 300.

' the appetite.

Case 2-Tabercalar meningizis..A long course of calcium treatmentassociated with streptomycin was carried out followed by treatment withisoniazide, the patient was cured. After days of calciumsulphosuccinate, the increase in weight was 2 kg. 900.

Case 3Discal sciatica.Calcium sulphosuccinate had a beneficial effect onthe general conditions of the patient and the pain was somewhatmodified. Increase in weight of 3 kg. in 15 days.

Case 4-Goitre without endocrine trouble in an unstable nearotonz'cpatient.-Increase in weight of 1 kg. 400m 15 days.

Case 5Cantractare, probably hysterical, of the right upper member.-Greatimprovement in the psychiatric syndrome (psychotherapy and isolationcombined). Increase in weight of 1 kg. 400 in 12 days.

Case 6Emaciati0n and asthenia connected partially with the socialqaesti0n.Considerable improvement in Increase in weight of 2 kg. 200 in1 month.

In general, the composition according to the invention has a favourablesthenic effect, generally leads to an improvement in the appetite, hassedative eifect on the neurovegetative system, and is useful in minoranxiety cases.

Example 7 Treatment with calcium sulphosuccinate produced the followingresults, in association with other medicaments.

Case 7Serz'0zls nutritional anaemia.Great improvement through treatmentwith folic acid and additional calcium treatment. After 45 days oftreatment under the conditions in Example 5 with calciumsulphosuccinate, the increase in weight was 5 kg. 700.

Case 8Hyperthyr0idism.2l days of injections of calcium sulphosuccinateafter a course of treatment with radioactive iodine. There was a verygreat improvement in the clinical condition, weight (increase of 3 kg.700) and neurotonic.

What I claim is:

1. An injectahle pharmaceutical composition for calcium therapycomprising a 5% solution of the neutral calcium salt of sulphosuccinicacid in sterile distilled water.

2. Method of treating calcium deficiencies which comprises administeringcalcium sulphosuccinate to a calcium-deficient subject.

References Cited in the file of this patent UNITED STATES PATENTS

1. AN INJECTABLE PHARMACEUTICAL COMPOSITION FOR CALCIUM THERAPYCOMPRISING A 5% SOLUTION OF THE NEUTRAL CALCIUM SALT OF SULPHOSUCCINICACID INSTERILE DISTILLED WATER.